Pathogens and dietary factors are transported across the gut epithelium. This poses a challenge of discriminating innocuous versus harmful antigens by innate and adaptive immune mechanisms. How B cells contribute to these processes is poorly understood. Moreover, recent studies indicate that B cells also undergo BCR diversification in the GALT, indicating that tolerance mechanisms need to be in place to eliminate newly arising autoreactive B cells. In the proposed work, we will use the conditional expression of a neo-self antigen to investigate B cell tolerance to epithelia-associated antigens in the GALT. This mouse model mimics the situation in some ulcerative colitis patients who produce auto-antibodies to antigens on epithelial cells of the colon. Proof-of-concept for the proposed studies is provided by our preliminary findings, showing that antigens expressed on the gut epithelia can efficiently eliminate self-reactive B cells. Here we will determine how and where these negative selection events take place, and how these processes are affected by a breach in the gut epithelial barrier as it relates to infection and inflammatory bowel disease.